tbuckley/cabot-search huggingface dataset:
First-line Treatment With Bendamustine and Rituximab for Old and Frail Patients With Aggressive Lymphoma: Results of the B-R-ENDA Trial
Authors: Friederike Braulke, Florian Zettl, Marita Ziepert, Andreas Viardot, Christoph Kahl, Gabriele Prange-Krex, Agnieszka Korfel, Martin Dreyling, Alexander Bott, Ulrich Wedding, Dietmar Reichert, Maike de Wit, Frank Hartmann, Viola Poeschel, Norbert Schmitz, Mathias Witzens-Harig, Wolfram Klapper, Andreas Rosenwald, Gerald Wulf, Bettina Altmann, Lorenz Trümper
Journal: HemaSphere (2022)

The incidence of aggressive B-cell lymphomas increases with age, but for elderly or frail patients not eligible for doxorubicin-containing treatment standard therapy remains to be defined. In this prospective, multicenter, phase-2 B-R-ENDA trial, we investigated the feasibility, toxicity, and efficacy of 8 cycles rituximab combined with 6 cycles bendamustine (BR) in elderly or frail aggressive B-cell lymphoma patients: 39 patients aged &gt;80 years and 29 patients aged 61–80 years with elevated Cumulative Illness Rating Scalescore &gt;6 were included. Progression-free survival (PFS) and overall survival (OS) at 2 years were 45% (95% confidence interval [CI], 28%-61%) and 46% (28%-63%) for the patients age &gt;80, as well 32% (13%-51%) and 37% (17%-57%) for frail patients age 64–80, respectively. In a preplanned retrospective analysis, we found no significant differences in PFS and OS comparing the outcome of the 39 patients age &gt;80 years with 40 patients aged 76–80 years treated with 6xR-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and 2 x rituximab in the RICOVER-60 trial (DSHNHL 1999-1, NCT00052936, EU-20243), yet we detected lower rates of infections and treatment-related deaths in the BR-treated patients. We demonstrate that older and frail patients with aggressive B-cell lymphoma who are not able to receive standard CHOP-based therapy can benefit from anthracycline-free therapy as a feasible and effective therapeutic option.
Interventional gastroenterology in oncology
Authors: Vaibhav Wadhwa, Nicole Patel, Dheera Grover, Faisal S. Ali, Nirav Thosani
Journal: CA A Cancer Journal for Clinicians (2022)

Abstract Cancer is one of the foremost health problems worldwide and is among the leading causes of death in the United States. Gastrointestinal tract cancers account for almost one third of the cancer‐related mortality globally, making it one of the deadliest groups of cancers. Early diagnosis and prompt management are key to preventing cancer‐related morbidity and mortality. With advancements in technology and endoscopic techniques, endoscopy has become the core in diagnosis and management of gastrointestinal tract cancers. In this extensive review, the authors discuss the role endoscopy plays in early detection, diagnosis, and management of esophageal, gastric, colorectal, pancreatic, ampullary, biliary tract, and small intestinal cancers.
Tunable Conductive Hydrogel Scaffolds for Neural Cell Differentiation
Authors: Christina M. Tringides, Marjolaine Boulingre, Andrew Khalil, Tenzin Lungjangwa, Rudolf Jaenisch, David J. Mooney
Journal: Advanced Healthcare Materials (2022)

Multielectrode arrays would benefit from intimate engagement with neural cells, but typical arrays do not present a physical environment that mimics that of neural tissues. It is hypothesized that a porous, conductive hydrogel scaffold with appropriate mechanical and conductive properties could support neural cells in 3D, while tunable electrical and mechanical properties could modulate the growth and differentiation of the cellular networks. By incorporating carbon nanomaterials into an alginate hydrogel matrix, and then freeze-drying the formulations, scaffolds which mimic neural tissue properties are formed. Neural progenitor cells (NPCs) incorporated in the scaffolds form neurite networks which span the material in 3D and differentiate into astrocytes and myelinating oligodendrocytes. Viscoelastic and more conductive scaffolds produce more dense neurite networks, with an increased percentage of astrocytes and higher myelination. Application of exogenous electrical stimulation to the scaffolds increases the percentage of astrocytes and the supporting cells localize differently with the surrounding neurons. The tunable biomaterial scaffolds can support neural cocultures for over 12 weeks, and enable a physiologically mimicking in vitro platform to study the formation of neuronal networks. As these materials have sufficient electrical properties to be used as electrodes in implantable arrays, they may allow for the creation of biohybrid neural interfaces and living electrodes.
Quantifying the Value of Multigene Testing in Resected Early Stage Lung Adenocarcinoma
Authors: Bharathi Muthusamy, Kira Raskina, Katherine T. Lofgren, Gerald Li, Khaled Tolba, Karen Schwed, Emily Castellanos, Richard S.P. Huang, Geoffrey R. Oxnard, Alexa B. Schrock, Nathan Pennell
Journal: Journal of Thoracic Oncology (2022)

Tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs), each requiring testing for precision biomarkers, have recently been approved in the adjuvant setting. We assessed the potential value of multigene testing in early lung adenocarcinoma (LUAD).Using a real-world clinicogenomic database linking deidentified electronic health record-derived clinical data to genomic data, we selected patients with LUAD who underwent tissue comprehensive genomic profiling (CGP). Using a probabilistic decision tree, we estimated the cost implications of the avoidance of adjuvant ICI in patients with programmed death-ligand 1-positive (PD-L1+) LUAD and an ALK, ROS1 or RET driver.The CGP was performed on a specimen collected before advanced disease in 20% (1320 of 6697) of cases and ordered before advanced diagnosis for 12.6% (847 of 6697) of patients. The prevalence of driver alterations in early and advanced-stage specimens was similar, though KRAS mutations were enriched in early disease and drivers including ALK rearrangements in advanced disease. Patients who had CGP results obtained before versus after recurrence had less time between recurrence and the start of any first-line treatment (median 3.6 versus 6 wk, p < 0.001). Through avoidance of ICI in programmed death-ligand 1-positive early LUAD with an ALK, ROS1 or RET driver, we estimated that the universal CGP could reduce expected costs by $1597.23 per patient relative to EGFR single-gene testing.The CGP can identify driver alterations and accelerate the start of first-line therapy at recurrence. It may also represent a cost-effective approach for avoiding futile adjuvant ICI in patients with drivers that have historically lacked activity with ICI in metastatic disease.
Utility of plasma cell-free DNA next-generation sequencing for diagnosis of infectious diseases in patients with hematological disorders
Authors: Chunhui Xu, Xin Chen, Guoqing Zhu, Huiming Yi, Shulian Chen, Yuetian Yu, Erlie Jiang, Yizhou Zheng, Fengkui Zhang, Jianxiang Wang, Sizhou Feng
Journal: Journal of Infection (2022)
CanRisk-Prostate: A Comprehensive, Externally Validated Risk Model for the Prediction of Future Prostate Cancer
Authors: Tommy Nyberg, Mark N. Brook, Lorenzo Ficorella, Andrew Lee, Joe Dennis, Xin Yang, Naomi Wilcox, Tokhir Dadaev, Koveela Govindasami, Michael Lush, Goska Leslie, Artitaya Lophatananon, Kenneth Muir, Elizabeth Bancroft, Douglas F. Easton, Marc Tischkowitz, Zsofia Kote-Jarai, Rosalind Eeles, Antonis C. Antoniou
Journal: Journal of Clinical Oncology (2022)

Prostate cancer (PCa) is highly heritable. No validated PCa risk model currently exists. We therefore sought to develop a genetic risk model that can provide personalized predicted PCa risks on the basis of known moderate- to high-risk pathogenic variants, low-risk common genetic variants, and explicit cancer family history, and to externally validate the model in an independent prospective cohort.
Reply to Evans and Woodward
Authors: Christian P Kratz, Dmitrii Smirnov, Robert Autry, Natalie Jäger, Sebastian M Waszak, Anika Großhennig, Riccardo Berutti, Mareike Wendorff, Pierre Hainaut, Stefan M Pfister, Holger Prokisch, Tim Ripperger, David Malkin
Journal: JNCI Journal of the National Cancer Institute (2022)
A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome
Authors: Pedro Silva-Pinheiro, Christian D. Mutti, Lindsey Van Haute, Christopher A. Powell, Pavel A. Nash, Keira Turner, Michal Minczuk
Journal: Nature Biomedical Engineering (2022)

Abstract The development of curative treatments for mitochondrial diseases, which are often caused by mutations in mitochondrial DNA (mtDNA) that impair energy metabolism and other aspects of cellular homoeostasis, is hindered by an incomplete understanding of the underlying biology and a scarcity of cellular and animal models. Here we report the design and application of a library of double-stranded-DNA deaminase-derived cytosine base editors optimized for the precise ablation of every mtDNA protein-coding gene in the mouse mitochondrial genome. We used the library, which we named MitoKO, to produce near-homoplasmic knockout cells in vitro and to generate a mouse knockout with high heteroplasmy levels and no off-target edits. MitoKO should facilitate systematic and comprehensive investigations of mtDNA-related pathways and their impact on organismal homoeostasis, and aid the generation of clinically meaningful in vivo models of mtDNA dysfunction.
Population, Clinical, and Scientific Impact of National Cancer Institute's National Clinical Trials Network Treatment Studies
Authors: Joseph M. Unger, Michael LeBlanc, Suzanne George, Norman Wolmark, Walter J. Curran, Peter J. O'Dwyer, Mitchell D. Schnall, Robert S. Mannel, Sumithra J. Mandrekar, James J. Dignam, Robert J. Gray, Fengmin Zhao, Mariama Bah, Riha Vaidya, Charles D. Blanke
Journal: Journal of Clinical Oncology (2022)

PURPOSE In the United States, the National Cancer Institute National Cancer Clinical Trials Network (NCTN) groups have conducted publicly funded oncology research for 50 years. The combined impact of all adult network group trials has never been systematically examined. METHODS We identified randomized, phase III trials from the adult NCTN groups, reported from 1980 onward, with statistically significant findings for ≥ 1 clinical, time-dependent outcomes. In the subset of trials in which the experimental arm improved overall survival, gains in population life-years were estimated by deriving trial-specific hazard functions and hazard ratios to estimate the experimental treatment benefit and then mapping this trial-level benefit onto the US cancer population using registry and life-table data. Scientific impact was based on citation data from Google Scholar. Federal investment costs per life-year gained were estimated. The results were derived through December 31, 2020. RESULTS One hundred sixty-two trials comprised of 108,334 patients were analyzed, representing 29.8% (162/544) of trials conducted. The most common cancers included breast (34), gynecologic (28), and lung (14). The trials were cited 165,336 times (mean, 62.2 citations/trial/year); 87.7% of trials were cited in cancer care guidelines in favor of the recommended treatment. These studies were estimated to have generated 14.2 million (95% CI, 11.5 to 16.5 million) additional life-years to patients with cancer, with projected gains of 24.1 million (95% CI, 19.7 to 28.2 million) life-years by 2030. The federal investment cost per life-year gained through 2020 was $326 in US dollars. CONCLUSION NCTN randomized trials have been widely cited and are routinely included in clinical guidelines. Moreover, their conduct has predicted substantial improvements in overall survival in the United States for patients with oncologic disease, suggesting they have contributed meaningfully to this nation's health. These findings demonstrate the critical role of government-sponsored research in extending the lives of patients with cancer.
Interpretation of Diaphragmatic Force Measurements in Reverse Triggering in a Porcine Model
Authors: Myrte Wennen, Annemijn H. Jonkman, Leo Heunks
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

treatment.Higher antimicrobial exposures (e.g., 100% fT .MIC (Percent of time free drug remains above the minimum inhibitory concentration) or 100% fT .2-5 3 MIC ) are likely needed for patients on ECMO who commonly demonstrate higher degrees of sickness severity and are likely infected with less susceptible pathogens (2).We agree that the link between antimicrobial exposures and clinical outcomes in this patient population should be better defined.Li and colleagues made a pertinent point on the limitations of the Cockcroft-Gault equation ( 9) when estimating creatinine clearance in critically ill patients and the potential for underestimation of creatinine clearance, especially in patients with augmented renal clearance.Although a significant proportion (46% venovenous ECMO and 61% venoarterial ECMO) of patients on ECMO have a degree of acute kidney injury (10), many others may potentially exhibit augmented renal clearance.More targeted pharmacokinetic studies in the latter to establish whether optimal antimicrobial exposures can be achieved with standard dosing.However, on the basis of current evidence and the Antibiotic, Sedative, Analgesic, Pharmacokinetics ECMO study findings (1, 2), antimicrobial dosing in patients with ECMO support should generally align with the recommended dosing strategies for critically ill patients without ECMO support.Antimicrobial dosing in this patient population should use strategies that optimize exposures for critically ill patients, which may include therapeutic drug monitoring.
Reactive Oxygen Species‐Triggered Hydrogen Sulfide Release and Cancer‐Selective Antiproliferative Effect of Anethole Dithiolethione‐Containing Polymeric Micelles
Authors: André J. van der Vlies, Masoud Ghasemi, Bernadette M. Adair, James H. Adair, Enrique D. Gomez, Urara Hasegawa
Journal: Advanced Healthcare Materials (2022)

Abstract Hydrogen sulfide (H 2 S) is a gaseous signaling molecule in the human body and has attracted attention in cancer therapy due to its regulatory roles in cancer cell proliferation and migration. Accumulating evidence suggests that continuous delivery of H 2 S to cancer cells for extended periods of time suppresses cancer progression. However, one major challenge in therapeutic applications of H 2 S is its controlled delivery. To solve this problem, polymeric micelles are developed containing H 2 S donating‐anethole dithiolethione (ADT) groups, with H 2 S release profiles optimal for suppressing cancer cell proliferation. The micelles release H 2 S upon oxidation by reactive oxygens species (ROS) that are present inside the cells. The H 2 S release profiles can be controlled by changing the polymer design. Furthermore, the micelles that show a moderate H 2 S release rate exert the strongest anti‐proliferative effect in human colon cancer cells in in vitro assays as well as the chick chorioallantoic membrane cancer model, while the micelles do not affect proliferation of human umbilical vein endothelial cells. This study shows the importance of fine‐tuning H 2 S release profiles using a micelle approach for realizing the full therapeutic potential of H 2 S in cancer treatment.
Trial of Deferiprone in Parkinson’s Disease
Authors: David Devos, Julien Labreuche, Olivier Rascol, Jean-Christophe Corvol, Alain Duhamel, Pauline Guyon Delannoy, Werner Poewe, Yaroslau Compta, Nicola Pavese, Evžen Růžička, Petr Dušek, Bart Post, Bastiaan R. Bloem, Daniela Berg, Walter Maetzler, Markus Otto, Marie-Odile Habert, Stéphane Lehericy, Joaquim Ferreira, Richard Dodel, Christine Tranchant, Alexandre Eusebio, Stéphane Thobois, Ana-Raquel Marques, Wassilios G. Meissner, Fabienne Ory-Magne, Uwe Walter, Rob M.A. de Bie, Miguel Gago, Dolores Vilas, Jaime Kulisevsky, Cristina Januario, Miguel V.S. Coelho, Stefanie Behnke, Paul Worth, Klaus Seppi, Thavarak Ouk, Camille Potey, Céline Leclercq, Romain Viard, Gregory Kuchcinski, Renaud Lopes, Jean-Pierre Pruvo, Pascal Pigny, Guillaume Garçon, Ophélie Simonin, Jessica Carpentier, Anne-Sophie Rolland, Dag Nyholm, Christoph Scherfler, Jean-François Mangin, Marie Chupin, Régis Bordet, David T. Dexter, Caroline Fradette, Michael Spino, Fernando Tricta, Scott Ayton, Ashley I. Bush, Jean-Christophe Devedjian, James A. Duce, Ioav Cabantchik, Luc Defebvre, Dominique Deplanque, Caroline Moreau
Journal: New England Journal of Medicine (2022)

Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear.
<i>RUNX1</i> isoform disequilibrium promotes the development of trisomy 21–associated myeloid leukemia
Authors: Sofia Gialesaki, Daniela Bräuer-Hartmann, Hasan Issa, Raj Bhayadia, Oriol Alejo-Valle, Lonneke Verboon, Anna-Lena Schmell, Stephanie Laszig, Enikő Regényi, Konstantin Schuschel, Maurice Labuhn, Michelle Ng, Robert Winkler, Christian Ihling, Andrea Sinz, Markus Glaß, Stefan Hüttelmaier, Sören Matzk, Lena Schmid, Farina Josepha Strüwe, Sofie-Katrin Kadel, Dirk Reinhardt, Marie-Laure Yaspo, Dirk Heckl, Jan-Henning Klusmann
Journal: Blood (2022)

Abstract Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR–CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.
Neonatal Outcomes after Use of Buprenorphine during Pregnancy
Authors: Elizabeth E Krans
Journal: New England Journal of Medicine (2022)

The opioid crisis in the United States has had profound effects on pregnant persons and their children. Over the past decade, the rate of opioid-related diagnoses during pregnancy has increased across nearly all states and demographic groups,1 and overdose is now a leading cause of pregnancy-related deaths.2 In pregnancy, the use of medications such as methadone and buprenorphine for opioid use disorder reduces the risks of overdose and preterm birth and is the recommended evidence-based treatment approach for pregnant persons with the disorder.3,4 For more than 30 years, methadone was the medication that was predominantly used to treat opioid use . . .
Bimekizumab in patients with psoriatic arthritis, naive to biologic treatment: a randomised, double-blind, placebo-controlled, phase 3 trial (BE OPTIMAL)
Authors: Iain B McInnes, Akihiko Asahina, Laura C Coates, Robert Landewé, Joseph F Merola, Christopher T Ritchlin, Yoshiya Tanaka, Laure Gossec, Alice B Gottlieb, Richard B Warren, Barbara Ink, Deepak Assudani, Rajan Bajracharya, Vishvesh Shende, Jason Coarse, Philip J Mease
Journal: The Lancet (2022)

Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17A and IL-17F. We assessed the efficacy and safety of bimekizumab in patients with active psoriatic arthritis who were naive to biologic disease-modifying antirheumatic drugs (DMARDs).BE OPTIMAL was a 52-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, active reference (adalimumab) trial done at 135 sites (hospitals, clinics, doctors' offices, and research centres) in 14 countries. Eligible patients were 18 years or older with a documented diagnosis of adult-onset psoriatic arthritis that met the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening. Participants were randomly assigned with an interactive-voice and web-response system on the basis of a predetermined randomisation schedule (3:2:1, stratified by region and bone erosion number at baseline) to bimekizumab 160 mg every 4 weeks, placebo every 2 weeks, or the reference group (adalimumab 40 mg every 2 weeks), all administered subcutaneously. At week 16, patients randomly assigned to placebo switched to bimekizumab 160 mg every 4 weeks. The primary endpoint was the proportion of patients reaching 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses included all patients who were randomly assigned (intention-to-treat population); the safety analysis set comprised patients who received one or more doses of treatment. Data are presented to week 24 (preplanned analysis). This trial is registered at ClinicalTrials.gov, NCT03895203.Between April 3, 2019, and Oct 25, 2021, 1163 patients were screened and 852 were randomly assigned to bimekizumab (n=431), placebo (n=281), and reference (adalimumab; n=140) groups. At week 16, significantly more patients receiving bimekizumab (189 [44%] of 431) reached ACR50 response versus placebo (28 [10%] of 281; odds ratio 7·1 [95% CI 4·6-10·9], p<0·0001; adalimumab 64 [46%] of 140). All secondary hierarchical endpoints were met. Treatment-emergent adverse events up to week 16 were reported in 258 [60%] of 431 patients receiving bimekizumab, 139 [49%] of 281 patients receiving placebo, and 83 [59%] of 140 patients receiving adalimumab. No deaths occurred.Bimekizumab treatment had superior improvements in joint, skin, and radiographic efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis who were naive to biologic DMARDs. The safety profile of bimekizumab, including the occurrence of fungal infections, was consistent with previous phase 3 studies in patients with plaque psoriasis, and with IL-17A inhibitors.UCB Pharma.
Molecular Classification of Appendiceal Adenocarcinoma
Authors: Michael B. Foote, Henry Walch, Walid Chatila, Efsevia Vakiani, Chris Chandler, Felix Steinruecke, Garrett M. Nash, Zsofia Stadler, Sebastian Chung, Rona Yaeger, Maria Ignez Braghrioli, Jinru Shia, Yelena Kemel, Anna Maio, Margaret Sheehan, Benoit Rousseau, Guillem Argilés, Michael Berger, David Solit, Nikolaus Schultz, Luis A. Diaz, Andrea Cercek
Journal: Journal of Clinical Oncology (2022)

Appendiceal adenocarcinomas (ACs) are rare, histologically diverse malignancies treated as colorectal cancers despite having distinct biology and clinical behavior. To guide clinical decision making, we defined molecular subtypes of AC associated with patient survival, metastatic burden, and chemotherapy response.